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Stem cell technology for the study and treatment of motor neuron diseases

    J Simon Lunn

    University of Michigan Department of Neurology, 109 Zina Pitcher Place, 5017 BSRB, Ann Arbor, MI 48109, USA

    ,
    Stacey A Sakowski

    University of Michigan Department of Neurology, 109 Zina Pitcher Place, 5017 BSRB, Ann Arbor, MI 48109, USA

    ,
    Thais Federici

    Department of Neurosurgery, Emory University, Atlanta, GA, USA

    ,
    Jonathan D Glass

    Department of Neurology, Emory University, Atlanta, GA, USA

    ,
    Nicholas M Boulis

    Department of Neurosurgery, Emory University, Atlanta, GA, USA

    &
    Published Online:https://doi.org/10.2217/rme.11.6

    Amyotrophic lateral sclerosis and spinal muscular atrophy are devastating neurodegenerative diseases that lead to the specific loss of motor neurons. Recently, stem cell technologies have been developed for the investigation and treatment of both diseases. Here we discuss the different stem cells currently being studied for mechanistic discovery and therapeutic development, including embryonic, adult and induced pluripotent stem cells. We also present supporting evidence for the utilization of stem cell technology in the treatment of amyotrophic lateral sclerosis and spinal muscular atrophy, and describe key issues that must be considered for the transition of stem cell therapies for motor neuron diseases from bench to bedside. Finally, we discuss the first-in-human Phase I trial currently underway examining the safety and feasibility of intraspinal stem cell injections in amyotrophic lateral sclerosis patients as a foundation for translating stem cell therapies for various neurological diseases.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Vazin T, Freed WJ: Human embryonic stem cells: derivation, culture, and differentiation: a review. Restor. Neurol. Neurosci.28(4),589–603 (2010).
    • Murry CE, Keller G: Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell132(4),661–680 (2008).
    • Kim SU: Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology24(3),159–171 (2004).
    • Xu L, Yan J, Chen D et al.: Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation82(7),865–875 (2006).▪▪ Demonstrates the therapeutic efficacy of human neural stem cells in the amyotrophic lateral sclerosis rat model, which provides support for the use of these cells in the current trial.
    • Garzon-Muvdi T, Quinones-Hinojosa A: Neural stem cell niches and homing: recruitment and integration into functional tissues. ILAR J.51(1),3–23 (2009).
    • Caplan AI: Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J. Cell Physiol.213(2),341–347 (2007).
    • Mezey E, Mayer B, Nemeth K: Unexpected roles for bone marrow stromal cells (or MSCs): a real promise for cellular, but not replacement, therapy. Oral Dis.16(2),129–135 (2010).
    • Robinson AP, Foraker JE, Ylostalo J, Prockop DJ: Human stem/progenitor cells from bone marrow enhance glial differentiation of rat neural stem cells: a role for transforming growth factor-β and Notch signaling. Stem Cells Dev.20(2),289–300 (2010).
    • Li JM, Zhu H, Lu S et al.: Migration and differentiation of human mesenchymal stem cells in the normal rat brain. Neurol. Res.33(1),84–92 (2010).
    • 10  Lunn JS, Hefferan MP, Marsala M, Feldman EL: Stem cells: comprehensive treatments for amyotrophic lateral sclerosis in conjunction with growth factor delivery. Growth Factors27(3),133–140 (2009).
    • 11  Hu BY, Zhang SC: Directed differentiation of neural-stem cells and subtype-specific neurons from hESCs. Methods Mol. Biol.636,123–137 (2010).
    • 12  Guo X, Johe K, Molnar P, Davis H, Hickman J: Characterization of a human fetal spinal cord stem cell line, NSI-566RSC, and its induction to functional motoneurons. J. Tissue Eng. Regen. Med.4(3),181–193 (2010).
    • 13  Hu BY, Zhang SC: Differentiation of spinal motor neurons from pluripotent human stem cells. Nat. Protoc.4(9),1295–1304 (2009).
    • 14  Thonhoff JR, Ojeda L, Wu P: Stem cell-derived motor neurons: applications and challenges in amyotrophic lateral sclerosis. Curr. Stem Cell Res. Ther.4(3),178–199 (2009).
    • 15  Jordan PM, Ojeda LD, Thonhoff JR et al.: Generation of spinal motor neurons from human fetal brain-derived neural stem cells: role of basic fibroblast growth factor. J. Neurosci. Res.87(2),318–332 (2009).
    • 16  Lepore AC, Rauck B, Dejea C et al.: Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat. Neurosci.11(11),1294–1301 (2008).
    • 17  Suzuki M, Svendsen CN: Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis. Trends Neurosci.31(4),192–198 (2008).
    • 18  Feldman EL, Goldman L, Ausiello D: Amyotrophic lateral sclerosis and other motor neuron diseases. In: Cecil Textbook of Medicine. Saunders, PA, USA, 2316–2319 (2004).
    • 19  Rosen DR, Siddique T, Patterson D et al.: Mutations in Cu/Zn superoxide dismutase are associated with familial amyotrophic lateral sclerosis. Nature362,59–62 (1993).
    • 20  Gonzalez DE, Aguilar JL, Echaniz-Laguna A et al.: Amyotrophic lateral sclerosis: all roads lead to Rome. J. Neurochem.101(5),1153–1160 (2007).
    • 21  Turner BJ, Talbot K: Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog. Neurobiol.85(1),94–134 (2008).
    • 22  Ilieva H, Polymenidou M, Cleveland DW: Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol.187(6),761–772 (2009).
    • 23  Kabashi E, Valdmanis PN, Dion P et al.: TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet.40(5),572–574 (2008).
    • 24  Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al.: Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science323(5918),1205–1208 (2009).
    • 25  Lagier-Tourenne C, Cleveland DW: Rethinking ALS: the FUS about TDP-43. Cell136(6),1001–1004 (2009).
    • 26  Sreedharan J, Blair IP, Tripathi VB et al.: TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science319(5870),1668–1672 (2008).
    • 27  Howland DS, Liu J, She Y et al.: Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc. Natl Acad. Sci. USA99,1604–1609 (2002).
    • 28  Gurney Me, Pu H, Chiu Ay et al.: Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science264(5166),1772–1775 (1994).
    • 29  Stallings NR, Puttaparthi K, Luther CM, Burns DK, Elliott JL: Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol. Dis.40(2),404–414 (2010).
    • 30  Festoff BW, Suo Z, Citron BA: Prospects for the pharmacotherapy of amyotrophic lateral sclerosis: old strategies and new paradigms for the third millennium. CNS Drugs17,699–717 (2003).
    • 31  Raoul C, Bbas-Terki T, Bensadoun JC et al.: Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat. Med.11,423–428 (2005).
    • 32  Rothstein JD, Patel S, Regan MR et al.: β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature433,73–77 (2005).
    • 33  Ji HF, Shen L, Zhang HY: β-lactam antibiotics are multipotent agents to combat neurological diseases. Biochem. Biophys. Res. Commun.333,661–663 (2005).
    • 34  Schutz B, Reimann J, Dumitrescu-Ozimek L et al.: The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J. Neurosci.25,7805–7812 (2005).
    • 35  Crow JP, Calingasan NY, Chen J, Hill JL, Beal MF: Manganese porphyrin given at symptom onset markedly extends survival of ALS mice. Ann. Neurol.58,258–265 (2005).
    • 36  Park JH, Hong YH, Kim HJ et al.: Pyruvate slows disease progression in a G93A SOD1 mutant transgenic mouse model. Neurosci. Lett.413(3),265–269 (2007).
    • 37  Bilic E, Rudan I, Kusec V, Zurak N, Delimar D, Zagar M: Comparison of the growth hormone, IGF-1 and insulin in cerebrospinal fluid and serum between patients with motor neuron disease and healthy controls. Eur. J. Neurol.13(12),1340–1345 (2006).
    • 38  Moreau C, Devos D, Brunaud-Danel V et al.: Paradoxical response of VEGF expression to hypoxia in CSF of patients with ALS. J. Neurol. Neurosurg. Psychiatry77(2),255–257 (2006).
    • 39  Dodge JC, Treleaven CM, Fidler JA et al.: AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice. Mol. Ther.18(12),2075–2084 (2010).
    • 40  Dodge JC, Haidet AM, Yang W et al.: Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Mol. Ther.16(6),1056–1064 (2008).
    • 41  Lunn JS, Sakowski SA, Kim B, Rosenberg AA, Feldman EL: Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration. Dev. Neurobiol.69(13),871–884 (2009).
    • 42  Sakowski SA, Heavener SB, Lunn JS et al.: Neuroprotection using gene therapy to induce vascular endothelial growth factor-A expression. Gene Ther.16(11),1292–1299 (2009).
    • 43  Sakowski SA, Schuyler AD, Feldman EL: Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler.10(2),63–73 (2009).
    • 44  Borasio GD, Robberecht W, Leigh PN et al.: A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology51(2),583–586 (1998).
    • 45  A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III). Neurology52(7),1427–1433 (1999).
    • 46  Miller RG, Petajan JH, Bryan WW et al.: A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann. Neurol.39(2),256–260 (1996).
    • 47  Lai EC, Felice KJ, Festoff BW et al.: Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology49(6),1621–1630 (1997).
    • 48  Sorenson EJ, Windbank AJ, Mandrekar JN et al.: Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology71(22),1770–1775 (2008).
    • 49  Wee CD, Kong L, Sumner CJ: The genetics of spinal muscular atrophies. Curr. Opin. Neurol.23(5),450–458 (2010).
    • 50  Rochette CF, Gilbert N, Simard LR: SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum. Genet.108(3),255–266 (2001).
    • 51  Lorson CL, Rindt H, Shababi M: Spinal muscular atrophy: mechanisms and therapeutic strategies. Hum. Mol. Genet.19(R1),R111–R118 (2010).
    • 52  Coady TH, Shababi M, Tullis GE, Lorson CL: Restoration of SMN function: delivery of a trans-splicing RNA re-directs SMN2 pre-mRNA splicing. Mol. Ther.15(8),1471–1478 (2007).
    • 53  Schrank B, Gotz R, Gunnersen JM et al.: Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc. Natl Acad. Sci. USA94(18),9920–9925 (1997).
    • 54  Jablonka S, Schrank B, Kralewski M, Rossoll W, Sendtner M: Reduced survival motor neuron (smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. Hum. Mol. Genet.9(3),341–346 (2000).
    • 55  Park GH, Kariya S, Monani UR: Spinal muscular atrophy: new and emerging insights from model mice. Curr. Neurol. Neurosci. Rep.10(2),108–117 (2010).
    • 56  Hsieh-Li HM, Chang JG, Jong YJ et al.: A mouse model for spinal muscular atrophy. Nat. Genet.24(1),66–70 (2000).
    • 57  Monani UR, Sendtner M, Coovert DD et al.: The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn-/- mice and results in a mouse with spinal muscular atrophy. Hum. Mol. Genet.9(3),333–339 (2000).
    • 58  Gunaseeli I, Doss MX, Antzelevitch C, Hescheler J, Sachinidis A: Induced pluripotent stem cells as a model for accelerated patient- and disease-specific drug discovery. Curr. Med. Chem.17(8),759–766 (2010).
    • 59  Inoue H: Neurodegenerative disease-specific induced pluripotent stem cell research. Exp. Cell Res.316(16),2560–2564 (2010).
    • 60  Kiskinis E, Eggan K: Progress toward the clinical application of patient-specific pluripotent stem cells. J. Clin. Invest.120(1),51–59 (2010).
    • 61  Marchetto MC, Winner B, Gage FH: Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases. Hum. Mol. Genet.19(R1),R71–R76 (2010).
    • 62  Takahashi K, Tanabe K, Ohnuki M et al.: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell131(5),861–872 (2007).
    • 63  Yamanaka S, Blau HM: Nuclear reprogramming to a pluripotent state by three approaches. Nature465(7299),704–712 (2010).
    • 64  Yamanaka S: Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell1(1),39–49 (2007).
    • 65  Yamanaka S: Induction of pluripotent stem cells from mouse fibroblasts by four transcription factors. Cell Prolif.41(Suppl. 1),51–56 (2008).▪▪ Describes the first generation of induced pluripotent stem cells utilizing the Yamanaka factors.
    • 66  Zhou H, Ding S: Evolution of induced pluripotent stem cell technology. Curr. Opin. Hematol.17(4),276–280 (2010).
    • 67  Maherali N, Hochedlinger K: Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell3(6),595–605 (2008).
    • 68  Yu J, Hu K, Smuga-Otto K et al.: Human induced pluripotent stem cells free of vector and transgene sequences. Science324(5928),797–801 (2009).
    • 69  Yu J, Thomson JA: Pluripotent stem cell lines. Genes Dev.22(15),1987–1997 (2008).
    • 70  Kim D, Kim CH, Moon JI et al.: Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell4(6),472–476 (2009).
    • 71  Zhang N, An MC, Montoro D, Ellerby LM: Characterization of human Huntington’s disease cell model from induced pluripotent stem cells. PLoS Curr.2,RRN1193 (2010).
    • 72  Soldner F, Hockemeyer D, Beard C et al.: Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell136(5),964–977 (2009).
    • 73  Liu J, Verma PJ, Evans-Galea MV et al.: Generation of induced pluripotent stem cell lines from Friedreich ataxia patients. Stem Cell Rev. (2010) (Epub ahead of print).
    • 74  Dimos JT, Rodolfa KT, Niakan KK et al.: Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science321(5893),1218–1221 (2008).▪ Demonstrates the generation of induced pluripotent stem cells from an amyotrophic lateral sclerosis patient.
    • 75  Ebert AD, Yu J, Rose FF Jr et al.: Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature457(7227),277–280 (2009).▪ Demonstrates the generation of induced pluripotent stem cells from a patient with spinal muscular atrophy.
    • 76  Mikkelsen TS, Hanna J, Zhang X et al.: Dissecting direct reprogramming through integrative genomic analysis. Nature454(7200),49–55 (2008).
    • 77  Hu BY, Weick JP, Yu J et al.: Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl Acad. Sci. USA107(9),4335–4340 (2010).
    • 78  Kane NM, Nowrouzi A, Mukherjee S et al.: Lentivirus-mediated reprogramming of somatic cells in the absence of transgenic transcription factors. Mol. Ther.18(12),2139–2145 (2010).
    • 79  Meissner A: Epigenetic modifications in pluripotent and differentiated cells. Nat. Biotechnol.28(10),1079–1088 (2010).
    • 80  Rolletschek A, Wobus AM: Induced human pluripotent stem cells: promises and open questions. Biol. Chem.390(9),845–849 (2009).
    • 81  Stadtfeld M, Apostolou E, Akutsu H et al.: Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature465(7295),175–181 (2010).
    • 82  Polo JM, Liu S, Figueroa ME et al.: Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat. Biotechnol.28(8),848–855 (2010).
    • 83  Corti S, Locatelli F, Donadoni C et al.: Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues. Brain127(Pt 11),2518–2532 (2004).
    • 84  Corti S, Nizzardo M, Nardini M et al.: Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a model of amyotrophic lateral sclerosis. Hum. Mol. Genet.19(19),3782–3796 (2010).
    • 85  Mitrecic D, Nicaise C, Gajovic S, Pochet R: Distribution, differentiation, and survival of intravenously administered neural stem cells in a rat model of amyotrophic lateral sclerosis. Cell Transplant.19(5),537–548 (2010).
    • 86  Ohnishi S, Ito H, Suzuki Y et al.: Intra-bone marrow-bone marrow transplantation slows disease progression and prolongs survival in G93A mutant SOD1 transgenic mice, an animal model mouse for amyotrophic lateral sclerosis. Brain Res.1296,216–224 (2009).
    • 87  Garbuzova-Davis S, Willing AE, Zigova T et al.: Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J. Hematother. Stem Cell Res.12(3),255–270 (2003).
    • 88  Garbuzova-Davis S, Sanberg CD, Kuzmin-Nichols N et al.: Human umbilical cord blood treatment in a mouse model of ALS: optimization of cell dose. PLoS ONE3(6),e2494 (2008).
    • 89  Chi L, Ke Y, Luo C et al.: Motor neuron degeneration promotes neural progenitor cell proliferation, migration, and neurogenesis in the spinal cords of amyotrophic lateral sclerosis mice. Stem Cells24(1),34–43 (2006).
    • 90  Suzuki M, Mchugh J, Tork C et al.: GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS ONE2(1),e689 (2007).
    • 91  Xu L, Ryugo DK, Pongstaporn T, Johe K, Koliatsos VE: Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. J. Comp. Neurol.514(4),297–309 (2009).
    • 92  Park S, Kim HT, Yun S et al.: Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice. Exp. Mol. Med.41(7),487–500 (2009).
    • 93  Suzuki M, Mchugh J, Tork C et al.: Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS. Mol. Ther.16(12),2002–2010 (2008).▪▪ Describes the use of mesenchymal stem cells to deliver therapeutic growth factors in an amyotrophic lateral sclerosis model. It also demonstrates the efficacy of using stem cells in combination with growth factor therapy to protect both motor neurons and neuromuscular junctions.
    • 94  Corti S, Nizzardo M, Nardini M et al.: Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy. J. Clin. Invest.118(10),3316–3330 (2008).
    • 95  Corti S, Nizzardo M, Nardini M et al.: Embryonic stem cell-derived neural stem cells improve spinal muscular atrophy phenotype in mice. Brain133(Pt 2),465–481 (2010).▪▪ Demonstrates the use of neurons derived from embryonic stem cells to improve the lifespan of a spinal muscular atrophy mouse model.
    • 96  Hung CW, Liou YJ, Lu SW et al.: Stem cell-based neuroprotective and neurorestorative strategies. Int. J. Mol. Sci.11(5),2039–2055 (2010).
    • 97  Li JY, Christophersen NS, Hall V, Soulet D, Brundin P: Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends Neurosci.31(3),146–153 (2008).
    • 98  Raore B, Federici T, Taub J et al.: Cervical multilevel intraspinal stem cell therapy: assessment of surgical risks in Gottingen minipigs. Spine36(3),E164–E171 (2011).
    • 99  Cizkova D, Kakinohana O, Kucharova K et al.: Functional recovery in rats with ischemic paraplegia after spinal grafting of human spinal stem cells. Neuroscience147(2),546–560 (2007).
    • 100  Yan J, Xu L, Welsh AM et al.: Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord. PLoS Med.4(2),e39 (2007).
    • 101  Usvald D, Vodicka P, Hlucilova J et al.: Analysis of dosing regimen and reproducibility of intraspinal grafting of human spinal stem cells in immunosuppressed minipigs. Cell Transplant.19(9),1103–1122 (2010).
    • 102  Riley JP, Raore B, Taub JS, Federici T, Boulis NM: Platform and cannula design improvements for spinal cord therapeutics delivery. Neurosurgery (2011) (In Press).
    • 103  Chen L, Huang H, Zhang J et al.: Short-term outcome of olfactory ensheathing cells transplantation for treatment of amyotrophic lateral sclerosis. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi21(9),961–966 (2007).
    • 104  Deda H, Inci MC, Kurekci AE et al.: Treatment of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up. Cytotherapy11(1),18–25 (2009).
    • 105  Federici T, Riley J, Park J, Bain M, Boulis NM: Preclinical safety validation of a stabilized viral vector direct injection approach to the cervical spinal cord. Clin. Transl. Sci.2(2),165–167 (2009).
    • 106  Mazzini L, Ferrero I, Luparello V et al.: Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a Phase I clinical trial. Exp. Neurol.223(1),229–237 (2010).
    • 107  Riley J, Butler J, Park J et al.: Targeted spinal cord therapeutics delivery: Stabilized platform and MER guidance validation. Stereotact. Funct. Neurosurg.86(2),67–74 (2007).
    • 108  Karussis D, Karageorgiou C, Vaknin-Dembinsky A et al.: Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch. Neurol.67(10),1187–1194 (2010).
    • 109  Dantuma E, Merchant S, Sugaya K: Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res. Ther.1(5),37 (2010).
    • 110  Gogel S, Gubernator M, Minger SL: Progress and prospects: stem cells and neurological diseases. Gene Therapy18(1),1–6 (2011).
    • 111  Miller RH: The promise of stem cells for neural repair. Brain Res.1091(1),258–264 (2006).
    • 112  Webber DJ, Minger SL: Therapeutic potential of stem cells in central nervous system regeneration. Curr. Opin. Investig. Drugs5(7),714–719 (2004).
    • 113  Yu D, Silva GA: Stem cell sources and therapeutic approaches for central nervous system and neural retinal disorders. Neurosurg. Focus24(3–4),E11 (2008).
    • 114  Geron Corporation: World’s first clinical trial of human embryonic stem cell therapy cleared. Regen. Med.4(2),161 (2009).
    • 115  Lopez-Gonzalez R, Kunckles P, Velasco I: Transient recovery in a rat model of familial amyotrophic lateral sclerosis after transplantation of motor neurons derived from mouse embryonic stem cells. Cell Transplant.18(10),1171–1181 (2009).
    • 116  Corti S, Locatelli F, Papadimitriou D et al.: Neural stem cells LewisX+ CXCR4+ modify disease progression in an amyotrophic lateral sclerosis model. Brain130(Pt 5),1289–1305 (2007).
    • 117  Rizvanov AA, Guseva DS, Salafautdinov II et al.: Genetically modified human umbilical cord blood cells expressing vascular endothelial growth factor and fibroblast growth factor 2 differentiate into glial cells after transplantation into amyotrophic lateral sclerosis transgenic mice. Exp. Biol. Med. (Maywood)236(1),91–98 (2011).
    • 118  Kim H, Kim HY, Choi MR et al.: Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci. Lett.468(3),190–194 (2010).
    • 119  Hwang DH, Lee HJ, Park IH et al.: Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice. Gene Ther.16(10),1234–1244 (2009).
    • 120  Klein SM, Behrstock S, Mchugh J et al.: GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum. Gene Ther.16(4),509–521 (2005).